Early life exposure to natural or environmental estrogens predisposes to prostate carcinogenesis with aging in animal models. Epidemiology studies provide compelling evidence that similar estrogen reprogramming may occur during gestation in humans. We have shown that brief neonatal exposure to high or low-dose estradiol results in permanent changes in the adult rat prostate including onset of prostatic intraepithelial neoplasia. Recently, we also found that early life exposure to environmentally relevant levels of bisphenol A, a prevalent environmental estrogen found in plastics and epoxy resins, increases the susceptibility of the adult prostate to hormonal carcinogenesis. Our working hypothesis is that natural, synthetic or environmental estrogenic exposures at relevant doses during development may be a predisposing factor to prostatic carcinoma in the aging male and provide a developmental origin for this adult disease. We have identified epigenetic alterations in DNA methylation as a molecular basis for this developmental reprogramming event. The gene for phosphodiesterase 4 D4 (PDE4D4), which degrades cAMP, was permanently hypomethylated following neonatal estradiol/BPA exposure resulting in increased PDE4D4 gene expression which may contribute to carcinogenisis. This insight provides a unique opportunity for early intervention with the goal of reversing estrogenic reprogramming of this gland. Methyl donor availability in the diet can directly influence gene methylation. The present proposal will investigate an intervention strategy with maternal dietary folate supplementation aimed at negating the adverse estrogenic effects on the prostate gland. Two Specific Aims are proposed: Aim 1: Determine whether maternal dietary supplementation with methyl donors during early development can reverse the neonatal estrogen-induced precancerous prostate lesions. Aim 2: Determine whether maternal dietary folate can reverse the estrogen-induced PDE4D4 hypomethylation with increased expression associated with carcinogenesis. We predict that these maternal feeding studies throughout gestation and lactation will effectively prevent, reverse or retard the onset of precancerous lesions in the adult prostate gland as a function of early exposure to elevated estradiol or an environmentally relevant dose of BPA. If such is the case, this will provide an effective and simple intervention for pregnant mothers and those feeding newborns who are currently concerned about unintended exposure to environmental estrogenic compounds. Principal Investigator: Prins, Gail S. Project Narrative There is increasing evidence that a number of adult diseases may have a fetal basis of origin and this may apply to the prostate gland regarding fetal estrogenic exposures and increased risk of prostate cancer with aging. Evidence indicates an epigenetic basis for estrogen reprogramming involving alterations in DNA methylation patterns. Maternal dietary supplementation during gestation and lactation with methyl donors such as folate and vitamin B12 may be capable of reversing the estrogen-induced methylation alterations and subsequent pathology in the prostate gland. Such findings would support the use of dietary supplements in pregnant mothers to counteract human exposures to prevalent environmental endocrine disruptors (e.g. BPA) with suspected carcinogenic potential.